The first goal of this research program is to study the biochemical pathogenesis of the effects of lead in the immature brain. The second and related goal is to understand the mechanism(s) by which the brain, with maturation, becomes resistant to lead encephalopathy. We shall use the rat pup, a model in which lead feedings produce a predominately cerebellar encephalopathy with pathologic changes and an age-specificity similar to those seen in the human. Derived from our previous results, we hypothesize that lead acts directly upon mitochondrial and, thus, cellular respiration. This effect may occur in all or only certain critical cell types in the immature cerebellum. The second hypothesis is that with maturation the mitochondrion is protected from accumulating toxic quantities of lead, possibly due to sequestration of lead in a developmentally appearing cellular or subcellular compartment. The research plan is to test these hypotheses in parallel studies of the metabolic and pathologic effects of lead and its distribution in the brain in situ, in isolated cell systems, and in isolated mitochondria. In studies of the cerebellum in situ, the effects of controlled lead feedings to pups from 14 days of age (encephalopathy-sensitive) will be compared to effects in pups fed lead from 18 or 20 days of age (encephalopathy-resistant). This design is intended to study the smallest age-difference between encephalopathic and non-encephalopathic animals in order to minimize age-dependent differences irrelevant to the genesis of lead encephalopathy. The in vitro effects and distribution of lead will be studied in brain slices, separated cerebellar cells (astrocytes and granular neurons), cultured astrocytes, and mitochondria. These studies are designed to study the mechanisms of cellular toxicity as well as any differences in this toxicity correlated with age, cell type, and brain region. Morphologic effects in situ and in vitro will be studied by light and electron microscopy. Effects of lead on cellular and mitochondrial respiration will be studied polarographically. Lead uptake, distribution, and localization will be studied by atomic absorption spectroscopy and by x-ray dispersive elemental micro-analysis.